Decrements in mitochondrial function have been postulated to be involved in the pathogenesis of numerous retinal and optic nerve diseases, including age-related macular degeneration, diabetic retinopathy, and Leber's hereditary optic neuropathy (J. F. Rizzo, Neurology 45:11-16, 1995; M. J. Baron, et al., Invest. Ophthalmol. Visual Sci. 42:3016-3022, 2001; V. Carelli, et al., Neurochem. Int. 40:573-584, 2002). Decrements in mitochondrial function have also been postulated to be involved in the pathogenesis in methanol intoxication (M. M. Hayreh, et al., Neurotoxicity of the Visual System, eds. Merigan, W. & Weiss, B. (Raven, New York), pp. 35-53, 1980; G. Martin-Amat, et al., Arch. Ophthalmol. 95:1847-1850, 1977; M. T. Seme, et al., J. Pharmacol. Exp. Ther. 289:361-370, 1999; M. T. Seme, et al., Invest. Ophthalmol. Visual Sci. 42:834-841, 2001). Methanol intoxication produces toxic injury to the retina and optic nerve, frequently resulting in blindness. A toxic exposure to methanol typically results in the development of formic academia, metabolic acidosis, visual toxicity, coma, and, in extreme cases, death (J. T. Eells, Browning's Toxicity and Metabolism of Industrial Solvents: Alcohols and Esters, eds. Thurman, T. G. Kaufmann, F. C. (Elsevier, Amsterdam), Vol. IV, pp. 3-15, 1992; R. Kavet and K. Nauss, Crit. Rev. Toxicol. 21:21-50, 1990). Visual disturbances generally develop between 18 and 48 hours after methanol ingestion and range from misty or blurred vision to complete blindness. Both acute and chronic methanol exposure have been shown to produce retinal dysfunction and optic nerve damage clinically (J. T. Eells, supra, 1992; R. Kavet and K. Nauss, supra, 1990; J. Sharpe, et al., Neurology 32:1093-1100, 1982) and in experimental animal models (S. O. Ingemansson, Acta Ophthalmol. 158 (Supp):5-12, 1983; J. T. Eells, et al., Neurotoxicology 21:321-330, 2000; T. G. Murray, et al., Arch. Ophthalmol. 109:1012-1016, 1991; E. W. Lee, et al., Toxicol. Appl. Pharmacol. 128:199-206, 1994).
Formic acid is the toxic metabolite responsible for the retinal and optic nerve toxicity produced in methanol intoxication (M. M. Hayreh, et al., supra, 1980; G. Martin-Amat, et al., supra 1977; M. T. Seme, et al., supra, 1999; M. T. Seme, supra, 2001; G. Martin-Amat, et al., Toxicol. Appl. Pharmacol. 45:201-208, 1978). Formic acid is a mitochondrial toxin that inhibits cytochrome c oxidase, the terminal enzyme of the mitochondrial electron transport chain of all eukaryotes (P. Nicholls, Biochem. Biophys. Res. Commun. 67:610-616, 1975; P. Nicholls, Biochim. Biophys. Acta 430:13-29, 1976). Cytochrome oxidase is an important energy-generating enzyme critical for the proper functioning of almost all cells, especially those of highly oxidative organs, including the retina and brain (M. T. T. Wong-Riley, Trends Neurosci. 12:94-101, 1989). Previous studies in our laboratory have established a rodent model of methanol-induced visual toxicity and documented formate-induced mitochondrial dysfunction and retinal photoreceptor toxicity in this animal model (M. T. Seme, et al., supra, 1999; M. T. Seme, et al., supra, 2001; J. T. Eells, et al., supra, 2000; T. G. Murray, et al., supra, 1991).
Photobiomodulation by light in the red to near-IR range (630-1,000 nm) using low-energy lasers or light-emitting diode (LED) arrays has been shown to accelerate wound healing, improve recovery from ischemic injury in the heart, and attenuate degeneration in the injured optic nerve (H. T. Whelan, et al., J. Clin. Laser Med. Surg. 19:305-314, 2001; U. Oron, et al., Lasers Sur. Med. 28:204-211, 2001; E. M. Assa, et al., Brain Res. 476:205-212, 1989; M. J. Conlan, et al., J. Clin. Periodont. 23:492-496, 1996; W. Yu, et al., Lasers Surg. Med. 20:56-63, 1997; A. P. Sommer, et al., J. Clin. Laser Med. Surg. 19:27-33, 2001). At the cellular level, photoirradiation at low fluences can generate significant biological effects, including cellular proliferation, collagen synthesis, and the release of growth factors from cells (M. J. Conlan, et al., supra, 1996; T. Karu, J. Photochem. Photobiol. 49:1-17, 1999; M. C. P. Leung, et al., Lasers Surg. Med. 31:283-288, 2002). Our previous studies have demonstrated that LED photoirradiation at 670 nm (4 J/cm2) stimulates cellular proliferation in cultured cells and significantly improves wound healing in genetically diabetic mice (H. T. Whelan, et al., supra, 2001; A. P. Sommer, et al., supra, 2001). Despite its widespread clinical application, the mechanisms responsible for the beneficial actions of photobiomodulation have not been elucidated. Mitochondrial cytochromes have been postulated as photoacceptors for red to near-IR light energy and reactive oxygen species have been advanced as potential mediators of the biological effects of this light (Karu, supra, 1999; N. Grossman, et al., Lasers Surg. Med. 22:212-218, 1998).